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HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells

Christiane Knuefermann1, Yang Lu, Bolin Liu

  • 1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA.

Oncogene
|May 23, 2003
PubMed

Insights

The HER2/PI-3K/Akt pathway activates Akt, leading to multidrug resistance in breast cancer cells. Inhibiting PI-3K or Akt sensitizes cells to chemotherapy, suggesting Akt as a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Growth factor receptor signaling pathways are crucial in cancer cell survival and drug resistance.
  • Multidrug resistance (MDR) in cancer remains a significant challenge, limiting the efficacy of conventional chemotherapy.

Purpose of the Study:

  • To investigate the role of the HER2/PI-3K/Akt pathway in mediating multidrug resistance in human breast cancer cells.
  • To explore Akt as a potential molecular target for overcoming chemoresistance.

Main Methods:

  • Utilized HER2/HER3 expressing breast cancer cell lines (MCF7).
  • Employed HER2 transfection, dominant-negative expression vectors for PI-3K and Akt inhibition.
  • Assessed chemoresistance to paclitaxel, doxorubicin, 5-fluorouracil, etoposide, and camptothecin.
  • Investigated the effect of constitutively active Akt (DeltaPH-Akt1-farn).

Main Results:

  • HER2/HER3 expression correlated with higher Akt phosphorylation (activation).
  • HER2 transfection in MCF7 cells led to PI-3K-dependent Akt activation and increased resistance to multiple chemotherapeutic agents.
  • Inhibition of PI-3K or Akt sensitized cells to chemotherapy-induced apoptosis.
  • Constitutively active Akt conferred similar chemoresistance.

Conclusions:

  • Activation of Akt1 by the HER2/PI-3K pathway plays a critical role in conferring broad-spectrum chemoresistance in breast cancer.
  • Targeting Akt may represent a novel therapeutic strategy to improve treatment outcomes for breast cancer patients.

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